Arylamines as inhibitors of chemokine binding to US28

ABSTRACT

Methods for treating CMV and CMV-related diseases are provided that use compounds having the formula:  
                 
 
     wherein the subscripts m and n are each independently integers from 1 to 2; and the R groups are as defined in the specification.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH OR DEVELOPMENT

[0001] The United States government may have certain rights toinventions described herein pursuant to DARPA grant No.N66001-01-C-8009.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. ProvisionalApplication Serial No. 60/316,386, filed Aug. 30, 2001, the contents ofwhich are incorporated herein by reference.

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK.

[0003] NOT APPLICABLE

BACKGROUND OF THE INVENTION

[0004] Cytomegalovirus (CMV) is an important human pathogen and a majoropportunist which emerges to cause disease in the immuno-compromisedsuch as AIDS patients, neonates, and individuals who have been givenimmunosuppressive drugs as part of a transplantation regimen. In theseindividuals, the consequences of CMV in acute or re-emerging infectionscan be dire, including retinitis, encephalitis, and pneumocystis, amongother pathologies. Furthermore, in immuno-competent hosts, CMVestablishes a persistent lifelong infection through which it has beenlinked to a variety of inflammatory conditions including coronary arteryocclusion following heart transplant and atherectomy and restenosisfollowing angioplasty. CMV interacts with leukocytes during acuteinfection of the host as well as during lifelong latency. As such,leukocytes are important players in CMV-induced disease and have beenimplicated in the acute phase of infection as vehicles for disseminationof virus and as sites of residence during lifelong latency.

[0005] CMV harbors in its genome an open reading frame (ORF), designatedUS28, which encodes a protein that acts as a functional receptor forcertain human and viral chemokines. Upon infection of a cell by CMV,US28 is expressed on the surface of the infected cell and becomescapable of responding to chemokines in the environment. Because thevirus on its own is inherently non-motile, and because chemokines andtheir receptors encoded by human cells are known to regulate themigration of leukocytes and other cells through the body, CMV US28 isthought to be encoded by the virus to facilitate the dissemination ofCMV through the body during and after infection. Therefore, agents whichblock the binding of chemokines to US28 should prove useful ininhibiting viral dissemination during acute or re-emerging CMVinfection.

[0006] CMV US28 has been shown to bind a variety of human, murine, andvirus-encoded CC chemokines in a variety of assay formats. In addition,the CX3C chemokine, Fractalkine, binds with a very high affinity(K_(I)˜50 pM) to US28. Fractalkine is expressed on certain endothelialcell surfaces and on populations of dendritic cells (DC), and may thusdefine a portal through which CMV infected cells go from the circulationto the tissue space, as well as find residence in the DC.

[0007] Since the US28 receptor is expressed on cytomegalovirus infectedcells, and also in view of its ability to bind multiple chemokines, asmall molecule inhibitor for this receptor would have significant use asan anti-CMV agent.

SUMMARY OF THE INVENTION

[0008] In one aspect, the present invention provides methods fortreating or preventing viral dissemination from CMV infection. Themethods typically involve administering to a patient an effectiveformulation of one or more of the compounds of formula I:

[0009] wherein Ar is a substituted or unsubstituted 5-14 memberedheteroaryl group having from 1 to 5 heteroatoms as ring members, or asubstituted or unsubstituted (C₆-C₁₄)aryl group; L is a substituted orunsubstituted linkage having from two to fourteen contiguous chain atomsselected from the group consisting of C, N, O, P and S; and R¹ and R²are each independently selected from (C₁-C₄)alkyl, wherein the alkylportions of L, R¹ and R² are optionally substituted with from one tofour substituents selected from halo, OR′, SR′, S(O)pR′, and CO₂R′, inwhich R′ is H or a (C₁-C₄)alkyl group, and the subscript p is 1 or 2; orR¹ and R² are optionally combined with the nitrogen atom to which eachis attached to form a ring selected from aziridine, azetidine,pyrrolidine, piperidine, imidazoline, piperazine and morpholine, each ofthe rings being optionally substituted with from one to threesubstituents selected from (C₁-C₄)alkyl, phenyl, phenyl(C₁-C₄)alkyl,hydroxy, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl anddi(C₁-C₄)alkylamino(C₁-C₄)alkyl.

[0010] In a group of particularly preferred embodiments, the compoundshave the formula:

[0011] wherein the subscripts m and n are each independently integersfrom 1 to 2; R¹ and R² are as defined above for formula I; and R³ and R⁴are each independently selected from the group consisting of(C₁-C₄)alkyl, or when taken together with the nitrogen atom to whicheach is attached, form a ring selected from the group consisting ofaziridine, azetidine, pyrrolidine, piperidine, imidazoline, piperazineand morpholine, each of the rings being optionally substituted with fromone to three substituents selected from (C₁-C₄)alkyl, phenyl,phenyl(C₁-C₄)alkyl, hydroxy, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl and di(C₁-C₄)alkylamino(C₁-C₄)alkyl.

[0012] Additionally, the invention provides compositions of the abovecompounds in combination with a pharmaceutically acceptable carrier orexcipient.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] None

DETAILED DESCRIPTION OF THE INVENTION

[0014] Abbreviations and Definitions

[0015] The term “alkyl,” by itself or as part of another substituent,means, unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, and can include di- andmultivalent radicals, having the number of carbon atoms designated (i.e.C₁-C₁₀ means one to ten carbons). Examples of saturated hydrocarbonradicals include groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An “unsaturated alkyl” group(e.g., an alkenyl or alkynyl group) is one having one or more doublebonds or triple bonds. Examples of unsaturated alkyl groups includevinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers.

[0016] The term “alkylene” by itself or as part of another substituentmeans a divalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingeight or fewer carbon atoms.

[0017] The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy)are used in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

[0018] The term “heteroalkyl,” by itself or in combination with anotherterm, means, unless otherwise stated, a stable straight or branchedchain, or cyclic hydrocarbon radical, or combinations thereof,consisting of the stated number of carbon atoms and from one to threeheteroatoms selected from the group consisting of O, N, Si and S, andwherein the nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroatom(s) O,N and S may be placed at any interior position of the heteroalkyl group.The heteroatom Si may be placed at any position of the heteroalkylgroup, including the position at which the alkyl group is attached tothe remainder of the molecule. Examples include —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may beconsecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.Similarly, the term “heteroalkylene” by itself or as part of anothersubstituent means a divalent radical derived from heteroalkyl, asexemplified by —CH₂—CH₂—S—CH₂CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. Forheteroalkylene groups, heteroatoms can also occupy either or both of thechain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino,alkylenediamino, and the like). Still further, for alkylene andheteroalkylene linking groups, no orientation of the linking group isimplied.

[0019] The terms “cycloalkyl” and “heterocycloalkyl”, by themselves orin combination with other terms, represent, unless otherwise stated,cyclic versions of “alkyl” and “heteroalkyl”, respectively.Additionally, for heterocycloalkyl, a heteroatom can occupy the positionat which the heterocycle is attached to the remainder of the molecule.Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkylinclude 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

[0020] The terms “halo” or “halogen,” by themselves or as part ofanother substituent, mean, unless otherwise stated, a fluorine,chlorine, bromine, or iodine atom. Additionally, terms such as“haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. Forexample, the term “halo(C₁-C₄)alkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0021] The term “aryl” means, unless otherwise stated, apolyunsaturated, typically aromatic, hydrocarbon substituent which canbe a single ring or multiple rings (up to three rings) which are fusedtogether or linked covalently. The term “heteroaryl” refers to arylgroups (or rings) that contain from one to five heteroatoms selectedfrom N, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Aheteroaryl group can be attached to the remainder of the moleculethrough a heteroatom. Generally, the aryl groups will have from six tofourteen carbon atoms as ring members, while the heteroaryl groups willhave from six to fourteen ring members selected from carbon, nitrogen,sulfur and oxygen. Non-limiting examples of aryl and heteroaryl groupsinclude phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. When thearyl or heteroaryl groups are provided as being “substituted orunsubstituted” the substituents for each of the above noted aryl andheteroaryl ring systems are selected from the group of acceptablesubstituents described below.

[0022] For brevity, the term “aryl” when used in combination with otherterms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl andheteroaryl rings as defined above. Thus, the term “arylalkyl” is meantto include those radicals in which an aryl group is attached to an alkylgroup (e.g., benzyl, phenethyl, pyridylmethyl and the like) includingthose alkyl groups in which a carbon atom (e.g., a methylene group) hasbeen replaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

[0023] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are often noted as “substituted or unsubstituted” and willinclude substituents for each type of radical as provided below.

[0024] Substituents for the alkyl and heteroalkyl radicals (includingthose groups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″ R′″, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —CN and —NO₂ in a number ranging from zero to (2m′+1),where m′ is the total number of carbon atoms in such radical. R′, R″ andR′″ each independently refer to hydrogen, unsubstituted (C₁-C₈)alkyl andheteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C₁-C₄)alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.For example, —NR′R″ is meant to include 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “substituted alkyl” is meant toinclude groups such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl(e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

[0025] Similarly, substituents for the aryl and heteroaryl groups arevaried and are selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′,—R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′,—NR″C(O)₂R′, —NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C.(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, (C₁-C₈)alkyl and heteroalkyl, unsubstituted aryl andheteroaryl, (unsubstituted aryl)-(C₁-C₄)alkyl, and (unsubstitutedaryl)oxy-(C₁-C₄)alkyl.

[0026] Two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—,—O—, —CH₂— or a single bond, and q is an integer of from 0 to 2.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—,—NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 3. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)₂-X-(CH₂)_(t)—, where s and t are independently integers of from 0to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. Thesubstituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted (C₁-C₆)alkyl.

[0027] As used herein, the term “heteroatom” is meant to include oxygen(O), nitrogen (N), sulfur (S) and silicon (Si).

[0028] The term “pharmaceutically acceptable salts” is meant to includesalts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic,citric, tartaric, methanesulfonic, and the like. Also included are saltsof amino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

[0029] The neutral forms of the compounds may be regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

[0030] In addition to salt forms, the present invention providescompounds which are in a prodrug form. Prodrugs of the compoundsdescribed herein are those compounds that readily undergo chemicalchanges under physiological conditions to provide the compounds of thepresent invention. Additionally, prodrugs can be converted to thecompounds of the present invention by chemical or biochemical methods inan ex vivo environment. For example, prodrugs can be slowly converted tothe compounds of the present invention when placed in a transdermalpatch reservoir with a suitable enzyme or chemical reagent.

[0031] Certain compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms are equivalent to unsolvated forms and areintended to be encompassed within the scope of the present invention.Certain compounds of the present invention may exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated by the present invention and areintended to be within the scope of the present invention.

[0032] Certain compounds of the present invention possess asymmetriccarbon atoms (optical centers) or double bonds; the racemates,diastereomers, geometric isomers and individual isomers are all intendedto be encompassed within the scope of the present invention.

[0033] The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

[0034] General

[0035] In related co-owned application Ser. Nos. 09/944,163, 09/944,051and 09/944,049, all filed Aug. 30, 2001 and incorporated herein byreference, assays for identifying compounds useful for blocking CMVdissemination in a host were provided. Typically, these assays determinewhether the compound inhibits the binding of a chemokine to US28 or aUS28 fragment, and are run as a competitive binding assay using alabeled chemokine. A variety of chemokines are known to bind to US28 andare useful in such assays. Preferably, the chemokine is fractalkine andthe assay is a radioligand binding assay.

[0036] Following methods outlined in the above-noted applications,compounds have now been identified that are effective in therapeuticmethods involving the blocking of CMV dissemination in a host.

[0037] Description of the Embodiments

[0038] A. Methods of Treating CMV Infection

[0039] In one aspect, the present invention provides novel methods fortreating or preventing CMV infection or diseases associated with, orresultant from, CMV infection. Without intending to be bound by theory,it is believed that the compounds and compositions provided below, exerttheir effect by inhibiting US28-mediated viral dissemination. Themethods typically involve administering to a patient an effectiveformulation of one or more of the subject compounds or compositionsdescribed in more detail below (e.g., compounds of formula I).

[0040] The invention provides methods of using the compounds andcompositions described below to treat disease or provide medicinalprophylaxis to individuals who possess a compromised immune system orare expected to suffer immunosuppressed conditions, such as patientsprior to undergoing immunosuppressive therapy in connection with organtransplantation or anticancer chemotherapy. Additional methods areprovided for the treatment of CMV-associated diseases (e.g.,atherosclerosis or cardiovascular diseases) in non-immunocompromisedindividuals. These methods generally involve administering to the hostan effective amount of the subject compounds or pharmaceuticallyacceptable compositions.

[0041] The compositions and compounds described herein and thepharmaceutically acceptable salts thereof can be administered in anyeffective way such as via oral, parenteral or topical routes. Generally,the compounds are administered in dosages ranging from about 2 mg up toabout 2,000 mg per day, although variations will necessarily occurdepending on the disease target, the patient, and the route ofadministration. Preferred dosages are administered orally in the rangeof about 0.05 mg/kg to about 20 mg/kg, more preferably in the range ofabout 0.05 mg/kg to about 2 mg/kg, most preferably in the range of about0.05 mg/kg to about 0.2 mg per kg of body weight per day.

[0042] Therapeutic and prophylactic methods of this invention comprisethe step of treating patients in a pharmaceutically acceptable mannerwith those compounds or compositions. Such compositions may be in theform of tablets, capsules, caplets, powders, granules, lozenges,suppositories, reconstitutable powders, or liquid preparations, such asoral or sterile parenteral solutions or suspensions. Compounds of theinvention may also be administered via an intraocular implant fortreating retinitis as a result of CMV infection. In particular,compounds may be embedded in a polymer based implant which will berelease into the eye over an extended period of time.

[0043] Physicians will determine the dosage of the present therapeuticagents which will be most suitable. Dosages may vary with the mode ofadministration and the particular compound chosen. In addition, thedosage may vary with the particular patient under treatment. The dosageof the compound used in the treatment will vary, depending on viralload, the weight of the patient, the relative efficacy of the compoundand the judgment of the treating physician. Such therapy may extend forseveral weeks or months, in an intermittent or uninterrupted manner.

[0044] B. Compounds Which Block CMV Dissemination

[0045] Compounds that are useful in blocking CMV dissemination have beenidentified using the assays described below, and have been found topossess a structure of general formula I.

[0046] In one group of embodiments, the compounds have the formula I:

[0047] wherein Ar is a substituted or unsubstituted 5-14 memberedheteroaryl group or a substituted or unsubstituted (C₆-C₁₄)aryl group; Lis a substituted or unsubstituted linkage having from two to fourteencontiguous chain atoms selected from the group consisting of C, N, O, Pand S; and R¹ and R² are each independently selected from the groupconsisting of (C₁-C₄)alkyl; wherein any alkyl portions of L, R¹ and R²are optionally substituted with from one to four substituents selectedfrom halo, OR′, SR′, S(O)pR′, and CO₂R′, in which R′ is H or a(C₁-C₄)alkyl group and the subscript p is an integer of from 1 to 2; orR¹ and R² are optionally combined with the nitrogen atom to which eachis attached to form a ring selected from aziridine, azetidine,pyrrolidine, piperidine, imidazoline, piperazine and morpholine, each ofthe rings being optionally substituted with from one to threesubstituents selected from (C₁-C₄)alkyl, phenyl, phenyl(C₁-C₄)alkyl,hydroxy, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl anddi(C₁-C₄)alkylamino(C₁-C₄)alkyl.

[0048] In preferred embodiments, R¹ and R² are independently selectedfrom methyl, ethyl and n-propyl. More preferably R¹ and R² are bothethyl.

[0049] In other preferred embodiments, Ar is a substituted phenyl,substituted benzimidazole, substituted indole, substituted6,7-benzoquinoline or a substituted 6,7-benzoisoquinoline.

[0050] In still other preferred embodiments, L is a linking groupselected from —N═C(CH₃)—, —NH—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂—,—OCH₂CH(OH)CH₂— and —NHCH₂CH₂CH₂—. More preferably, L is—NH—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂—, —OCH₂CH(OH)CH₂— or —NHCH₂CH₂CH₂—.

[0051] In one group of particularly preferred embodiments, L is selectedfrom —N═C(CH₃)—, —NH—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂—, —OCH₂CH(OH)CH₂— and—NHCH₂CH₂CH₂—; R¹ and R² are each ethyl; and Ar is a substituted phenylhaving the formula:

[0052] wherein the subscript q is an integer of from 0 to 3; each R⁵ isa substituent independently selected from halogen, NO₂, CN, R, OR, NR₂,CO₂R, C(O)R, OC(O)R, NRC(O)R and NRC(O)NR₂, wherein each R isindependently selected from H and (C₁-C₈)alkyl; and R³ and R⁴ are eachindependently (C₁-C₄)alkyl or are optionally combined with the nitrogenatom to which each is attached to form a ring selected from aziridine,azetidine, pyrrolidine, piperidine, imidazoline, piperazine andmorpholine, each of the rings being optionally substituted with from oneto three substituents selected from (C₁-C₄)alkyl, phenyl,phenyl(C₁-C₄)alkyl, hydroxy, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl and di(C₁-C₄)alkylamino(C₁-C₄)alkyl. Stillfurther preferred are those embodiments in which L is selected from—NH—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂—, —OCH₂CH(OH)CH₂— and —NHCH₂CH₂CH₂—; R¹and R² are each ethyl; and Ar is a substituted phenyl having theformula:

[0053] wherein the subscript q is 1 or 2; each R⁵ is a substituentindependently selected from halogen, NO₂, CN, CO₂R and C(O)R, whereineach R is independently selected from H and (C₁-C₄)alkyl; and R³ and R⁴taken together with the nitrogen atom to which each is attached form a5- or 6-membered ring selected from pyrrolidine, piperidine andmorpholine.

[0054] In a group of particularly preferred embodiments, the compoundshave the formula:

[0055] wherein the subscripts m and n are each independently integersfrom 1 to 2; R¹ and R² are as defined above for formula I; and R³ and R⁴are each independently selected from the group consisting of(C₁-C₄)alkyl, or when taken together with the nitrogen atom to whicheach is attached, form a ring selected from the group consisting ofaziridine, azetidine, pyrrolidine and piperidine which is optionallysubstituted with one or two (C₁-C₄)alkyl groups.

[0056] Most preferred are the compounds having the formula:

[0057] with R¹, R², R³, R⁴ and n and m being selected from the preferredgroups above. Most preferred are those compounds provided in theExamples.

[0058] Within each of the groups of compounds above, evaluation ofefficacy can be accomplished by assays to determine whether the compoundinhibits the binding of a chemokine to US28 or a suitable US28 fragment.

[0059] Preparation of Compounds of Formula I

[0060] Compounds useful in the present methods and compositions can beprepared using generally accepted synthetic techniques starting withcommercially available materials (e.g., from Aldrich Chemical Co.,Milwaukee, Wis., USA or Fluka Chemical Co.).

[0061] Scheme I illustrates the preparation of compounds of formula I:

[0062] In this scheme, a di-substituted amine (g) is reacted withepichlorohydrin (h) to provide a linking group reagent (i). A suitablysubstituted aniline (j) is reacted with 1,4-dichlorobutane (k) to formthe N-phenyl pyrrolidine compound (l), having a phenolic hydroxy group.Reaction of I with i, under alkylating conditions provides compounds offormula m as one group of compounds of formula I. Other compounds offormula I can be prepared by substitution of various aniline derivatives(j), alkylating agents (k), and di-substituted amines (g). Similarly,epichlorohydrin can be replaced with other groups having suitablefunctionality to react with a phenolic hydroxy group as well as adi-substituted amine (g).

[0063] Following the outline of Scheme I, 2-amino-5-nitrophenol can betreated with 1,4-dichlorobutane to formN-(2-hydroxy-4-nitrophenyl)pyrrolidine (compound I in which thesubscript q is 1 and R⁵ is a nitro group in a position para to thepyrrolidine ring). Alkylation of the phenol with3-chloro-1-(N,N-diethylamino)-2-propanol provides compound I-a (seeTable in Example 3).

[0064] C. Assays for Identifying Compounds Which Block ViralDissemination

[0065] Assays are provided herein for identifying a compound capable ofblocking CMV dissemination in a host, by determining whether thecompound inhibits the binding of a chemokine to US28 or a US28 fragment.

[0066] These assays are typically cell-based assays in which a cellwhich stably expresses US28 is treated with a candidate compound, ormore preferably a compound having formula I above and a chemokine in acompetitive binding format. Selection of the most potent compounds canbe made according to established practices for receptor-ligandcompetitive binding studies. A variety of other assay formats are alsouseful in the present invention. For example, substrate-bound orsupport-bound chemokines (or ligands) can be contacted with a labeledcell or liposome having an associated US28 or US28 fragment

[0067] A variety of cell lines can be used in this aspect of theinvention. In one group of embodiments, the cell line is a mouse cellline. In other embodiments, the cell line is a human or primate cellline (e.g., human foreskin fibroblasts (HFF), human diploid lungfibroblasts (MRC-5 and WI-38), or HUVECs), 293 and COS-7 cells. The celllines described are transfected with US28 cDNA, typically under thecontrol of a CMV promoter, using conventional methods. The cell arecultured in a suitable buffer (e.g., IMDM-5% FBS, DMEM 10% FCS, HUVECcomplete medium, and the like) then centrifuged and resuspended in assaybuffer (e.g., HEPES with NaCl, CaCl₂, MgCl₂, and BSA) to a concentrationof from about 5×10⁵ to about 5×10⁷, preferably from about 2 to about8×10⁶. Aliquots of the cells are then contacted with the candidatecompounds and labeled chemokine.

[0068] A variety of chemokines can be used in this aspect of theinvention, including, for example, fractalkine, RANTES, MCP-3, MIP-1αand MCP-1. Preferably, the labeled chemokine is labeled fractalkine.Additionally, a variety of labels can also be used with the chemokinesdescribed above. Typically, the label will be a fluorescence label, aphosphorescence label, a radiolabel, a calorimetric label, or the like.In preferred embodiments the labeled chemokine is a radiolabeledfractalkine, more preferably, ¹²⁵I-fractalkine.

[0069] After contacting the cells with one or more candidate compoundsin the presence of labeled chemokine, the assay mixture is typicallyincubated for a period of time of from about 1 to about 6 hours at atemperature of from about 1 to about 10° C. Preferably the mixture isincubated for a period of from about 2 to about 4 hours at a temperatureof about 4° C. One of skill in the art will understand that a variety ofassay conditions can be employed, depending on the cell line used, theconcentrations of the compounds and chemokine and the concentration ofthe cells themselves.

[0070] Following incubation the assay wells (for those embodimentscarried out on 96-, 384-, 1536-well or larger plates) are typicallyharvested under vacuum using filter plates, pre-soaked with PEIsolution. Scintillation fluid (for radiolabel assays) is added, theplates are sealed and the wells are counted.

[0071] D. Compositions Useful in the Treatment of CMV Infection

[0072] The present invention also provides compositions useful forpreventing CMV dissemination in a host, which comprises apharmaceutically acceptable carrier or adjuvant and an effective amountof a compound identified using the assays described herein. Preferably,the compound is a compound of formula I.

[0073] Typically, the compositions contain from about 0.1% to about 99%by weight of active compound, and preferably from about 10% to about 60%by weight depending on which method of administration is employed.

[0074] A CMV dissemination-inhibiting amount is that amount of activecompound required to slow the progression of viral dissemination orreduce the amount of viral dissemination from that which would otherwiseoccur without administration of the compound. Or, it is an amount ofactive compound required to slow the progression or reduce the intensityof symptoms resulting from CMV infection or reactivation or eliminationthereof.

[0075] CMV dissemination-inhibiting activity of compounds of theinvention can be determined according to the assays described herein.The assays provide an indication of chemokine binding to US28, moretypically fractalkine binding to US28. The compounds provided hereininhibit the binding of fractalkine to US28 with activity expressed asIC50 (that amount of compound that reduces fractalkine binding by 50%).The compounds provided herein will typically exhibit an IC50 ofapproximately 50 μM or less, preferably 25 μM or less, more preferably10 μM or less, and most preferably less than 1 μM.

[0076] For the compositions of the invention, the proportion of eachcarrier, diluent or adjuvant is determined by the solubility andchemical nature of the compound and the route of administrationaccording to standard pharmaceutical practice. In order to obtainconsistency of administration, however, it is preferred that acomposition of the invention is in the form of a unit dose. For example,the unit dose presentation forms for oral administration may be tabletsand capsules and may contain conventional excipients such as bindingagents (e.g., acacia, gelatin, sorbitol, or polyvinylpyrrolidone),fillers (e.g., lactose, sugar, maize-starch, calcium phosphate, sorbitolor glycine), tableting lubricants (e.g., magnesium stearate),disintegrants (e.g., starch, polyvinylpyrrolidone, sodium starchglycoallate or microcrystalline cellulose), or pharmaceuticallyacceptable wetting agents (e.g., sodium lauryl sulfate).

[0077] The compounds may be injected parenterally; this beingintramuscularly, intravenously, or subcutaneously. For parenteraladministration, the compound may be used in the form of sterilesolutions containing other solutes, for example, sufficient saline orglucose to make the solution isotonic. The amount of active ingredientadministered parenterally will be approximately 0.01 to 250 mg/kg/day,preferably about 1 to 10 mg/kg/day, more preferably about 0.5 to 30mg/kg/day, and more most preferably about 1-20 mg/kg/day.

[0078] The compounds may be administered orally in the form of tablets,capsules, or granules containing suitable excipients such as starch,lactose, white sugar and the like. The compounds may be administeredorally in the form of solutions which may contain coloring and/orflavoring agents. The compounds may also be administered sublingually inthe form of tracheas or lozenges in which each active ingredient ismixed with sugar or corn syrups, flavoring agents and dyes, and thendehydrated sufficiently to make the mixture suitable for pressing intosolid form. The amount of active ingredient administered orally willdepend on bioavailability of the specific compound.

[0079] The solid oral compositions may be prepared by conventionalmethods of blending, filling, tableting, or the like. Repeated blendingoperations may be used to distribute the active agent throughout thosecompositions employing large quantities of tillers. Such operations are,of course, conventional in the art. The tablets may be coated accordingto methods well known in normal pharmaceutical practice, in particularwith an enteric coating.

[0080] Oral liquid preparations may be in the form of emulsions, syrups,or elixirs, or may be presented as a dry product for reconstitution withwater or other suitable vehicle before use. Such liquid preparations mayor may not contain conventional additives. For example suspendingagents, such as sorbitol, syrup, methyl cellulose, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, orhydrogenated edible fats; emulsifying agents, such as sorbitanmonooleate or acaci; non-aqueous vehicles (which may include edibleoils), such as almond oil, fractionated coconut oil, oily estersselected from the group consisting of glycerine, propylene glycol,ethylene glycol, and ethyl alcohol; preservatives, for instance methylpara-hydroxybenzoate, ethyl para-hydroxybenzoate, n-propylparahydroxybenzoate, or n-butyl parahydroxybenzoate of sorbic acid; and,if desired, conventional flavoring or coloring agents.

[0081] The compounds of the present invention may also be administeredin the form of suppositories for rectal administration of the drug.These compositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0082] For topical use, creams, ointments, jellies, solutions orsuspensions, etc., containing the compounds of the present invention areemployed. As used herein, topical application is also meant to includethe use of mouth washes and gargles.

[0083] In another embodiment, the invention provides the subjectcompounds in the form of a pro-drug, which can be metabolically orchemically converted to the subject compound by the recipient host. Awide variety of pro-drug derivatives are known in the art such as thosethat rely on hydrolytic cleavage or oxidative activation of the prodrug.

[0084] The compositions may be advantageously combined and/or used incombination with other antiviral agents which are either therapeutic orprophylactic agents, and different from the subject compounds. Thecompositions may also be advantageously combined and/or used incombination with agents that treat or induce conditions often associatedwith the viral infections that are sensitive to the present compounds,such as anti-HIV agents or immunosuppressive agents. In many instances,administration in conjunction with the subject compositions enhances theefficacy of such agents. Exemplary antiviral agents include ganciclovir,foscamet and cidofovir. Exemplary anti-HIV agents include indinavir,ritonavir, AZT, lamivudine and saquinavir. Exemplary immunosuppressiveagents include cyclosporin and FK-506. The compositions may also beadvantageously used as antiviral prophylactic treatment in combinationwith immunosuppressive protocols such as bone-marrow destruction (eitherby radiation or chemotherapy).

[0085] To further assist in understanding the present invention, thefollowing non-limiting examples are provided.

EXAMPLES Example 1

[0086] Radioligand binding assays were carried our in the followingmanner. The target cells typically used in these assays were eitherRhesus dermal fibroblasts which had been infected with Rhesus CMV for2-4 days, or hUS28 transfected murine cells. Lots of cells verified forfractalkine binding were frozen until use. For the assay, cells werethawed, washed, and resuspended in assay buffer (20 mM HEPES pH 7.1, 140mM NaCl, 1 mM CaCl₂, 5 mM MgCl₂, and with 0.2% bovine serum albumin) toa concentration of from 4×10⁵ to 5×10⁶ cells/mL. Compounds were preparedas 10×solutions in 20% DMSO, and 0.02 mL was placed in assay plates.Next 0.09 mL of cells was added to the assay plates containing thecompounds. Lastly 0.09 mL of ¹²⁵I-fractalkine diluted in assay buffer(final concentration ˜50 pM, with 20,000-50,000 cpm per well) was added,the plates sealed and incubated for 2-4 hours at 4° C. on a shakerplatform. The assay plates were harvested using Packard GF/B filterplates, pre-soaked in 0.3% polyethyleneimmine solution, on a Packardvacuum cell harvester. Scintillation fluid was added to all wells, theplates were sealed and counted in a Top Count scintillation counter.Control wells containing either diluent only (for total counts) orexcess unlabeled fractalkine (1 μg/mL, for non-specific binding) wereused to calculate the percent of total inhibition. IC₅₀ values are thoseconcentrations required to reduce the binding of labeled fractalkine tothe receptor by 50%, and were determined by nonlinear regressioncurve-fitting of the dose-response assays.

Example 2

[0087] This example illustrates one method for the preparation ofcompounds of formula I, from commercially available starting materials.

[0088] To a oven dry 1 L three-neck round bottom flask, was added NaH(40 g, 1.67 mol), dry DMF (150 mL) and cooled to 0° C.2-Methoxy-4-nitroaniline (50 g, 0.297 mol) in dry DMF (350 mL) was addedover 15 min at 0° C. The reaction mixture was warmed to room temperatureand stirring was continued for 1.5 hr. After cooling to 0° C.,1,4-dibromobutane (116 g, 0.54 mol) in dry DMF (150 mL) was added over15 min and stirring was continued for 15 hr at room temperature. Thereaction mixture was poured into ice water, the analytically pure redsolid product was filtered and dried under vacuum. Yield: 61 g, 92%.

[0089] Step-2:

[0090] Dry K₂CO₃ (10 g, 0.072 mol) in NMP (60 mL, 0.626 mol) was heatedto 165° C. for 1 hr under nitrogen.N-(2-Methoxy-4-nitrophenyl)pyrrolidine (20 g, 0.090 mol) and thiophenol(28 mL, 0.272 mol) were added with stirring at 165° C. Stirring wascontinued for 2 hr at 150° C. The mixture was cooled to roomtemperature, neutralized with 1.5 N HCl and extracted with ether. Theether layer was washed with water, brine, dried over Na₂SO₄ andconcentrated. The dark red product obtained was purified by columnchromatography using petroleum ether-ethylacetate (9:1) as eluent.Yield: 11.5 g, 61%.

[0091] Step-3:

[0092] N-(2-Hydroxy-4-nitrophenyl)pyrrolidine (5 g, 0.024 mol),racemic-epichlorohydrin (40 mL) and catalytic amount oftetrabutylammonium bromide (60 mg) in 100 mL 3N flask was heated at 50°C. with stirring for 30 min. NaOH (2.3 g, 0.058 mol) in water (5 mL) wasadded slowly over 15 min. Stirring was continued at 50° C. for 15 hr.Water (100 mL) was added, extracted with chloroform, washed with water,dried over Na₂SO₄ and concentrated. The crude epoxide was purified bycolumn chromatography using 9.5:0.5 petroleum ether:ethylacetate aseluent. Yield: 2.7 g, 43%.

[0093] Step-4:

[0094] A mixture of the epoxide derivative (200 mg, 0.00075 mol)obtained from the above step and an ethanolic solution of dimethylamine(10 mL, 2.0 M) was stirred at room temperature over night. Solvent wasevaporated and the yellow product was purified by column chromatographyusing chloroform as eluent. Yield: 70 mg, 30.4%.

[0095] Synthesis of I-b

[0096] Step-1:

[0097] N-(2-Hydroxy-4-nitrophenyl)pyrrolidine (3 g, 0.0144 mol),(S)-(+)-epichlorohydrin (1.4 g, 0.015 mol) and dry K₂CO₃ (2.6 g, 0.0187mol) in dry acetonitrile (40 mL) was stirred at 60° C. for overnight.Water (100 mL) was added, extracted with chloroform, washed with water,dried over Na₂SO₄ and concentrated. The red crude product was carried onto the next step without purification. Yield: 3.0 g, 78%.

[0098] Step-2.

[0099] The crude epoxide (100 mg, 0.00038 mol) and diethylamine (3 mL)was stirred at room temperature for overnight. The solution wasconcentrated and the yellow product was purified by columnchromatography using 0.2% methanol in chloroform as eluent. Yield: 60mg, 47%.

[0100] Synthesis of I-l

[0101] Step-1:

[0102] N-(2-Hydroxy-4-nitrophenyl)pyrrolidine (1.7 g, 0.008 mol),(R)-(−)-epichlorohydrin (0.74 g, 0.008 mol) and dry K₂CO₃ (1.35 g,0.0098 mol) in dry DMF (5 mL) was stirred at 55° C. for overnight. Water(50 mL) was added, extracted with chloroform, washed with water, driedover Na₂SO₄ and concentrated. The crude material was purified by columnchromatography using 3% ethylacetate in petroleum ether as eluent.Yield: 0.3 g, 14%.

[0103] Step-2:

[0104] The epoxide (100 mg, 0.00038 mol) and diethylamine (1.0 mL) indry isopropanol (10 mL) was stirred at room temperature overnight. Thesolution was concentrated and the yellow product was purified by columnchromatography using chloroform as eluent. Yield: 95 mg, 75%.

[0105] Synthesis of I-f

[0106] A mixture of the epoxide (100 mg, 0.00038 mol) derivative(obtained from Example 3) and diisopropylamine (2 mL) in isopropanol (5mL) was stirred at room temperature overnight. The yellow productobtained after the evaporation of the solvent was purified by columnchromatography using chloroform as eluent. Yield: 69 mg, 50%.

Example 3

[0107] The table below illustrates the activity associated with variouscompounds prepared by the methods described above and evaluation usingthe assays also provided above. hUS28 Compound IC₅₀ (μM)

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[0108] It is understood that the examples and embodiments describedherein are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication and scope of the appended claims. All publications, patents,and patent applications cited herein are hereby incorporated byreference for all purposes.

What is claimed is:
 1. A method for treating CMV or CMV-related diseasesin a host, comprising administering to said host an effective amount ofa compound of formula I:

wherein Ar is a substituted or unsubstituted 5-14 membered heteroarylgroup or a substituted or unsubstituted (C₆-C₁₄)aryl group; L is asubstituted or unsubstituted linkage having from two to fourteencontiguous chain atoms selected from the group consisting of C, N, O, Pand S; and R¹ and R² are each independently selected from the groupconsisting of (C₁-C₄)alkyl; wherein any alkyl portions of L, R¹ and R²are optionally substituted with from one to four substituents selectedfrom halo, OR′, SR′, S(O)pR′, and CO₂R′, in which R′ is H or a(C₁-C₄)alkyl group, and the subscript p is 1 or 2; or R¹ and R² areoptionally combined with the nitrogen atom to which each is attached toform a ring selected from aziridine, azetidine, pyrrolidine, piperidine,imidazoline, piperazine and morpholine, each of the rings beingoptionally substituted with from one to three substituents selected from(C₁-C₄)alkyl, phenyl, phenyl(C₁-C₄)alkyl, hydroxy, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl and di(C₁-C₄)alkylamino(C₁-C₄)alkyl.
 2. Amethod in accordance with claim 1, wherein R¹ and R² are each ethyl. 3.A method in accordance with claim 1, wherein Ar is selected from thegroup consisting of substituted phenyl, substituted benzimidazole,substituted indole, substituted 6,7-benzoquinoline, and substituted6,7-benzoisoquinoline.
 4. A method in accordance with claim 1, wherein Lis selected from the group consisting of —N═C(CH₃)—,—NH—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂—, —OCH₂CH(OH)CH₂— and —NHCH₂CH₂CH₂—.
 5. Amethod in accordance with claim 1, wherein L is selected from the groupconsisting of —N═C(CH₃)—, —NH—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂—,—OCH₂CH(OH)CH₂— and —NHCH₂CH₂CH₂—; R¹ and R² are each ethyl; and Ar is asubstituted phenyl having the formula:

wherein the subscript q is an integer of from 0 to 3; each R⁵ is asubstituent independently selected from the group consisting of halogen,NO₂, CN, R, OR, NR₂, CO₂R, C(O)R, OC(O)R, NRC(O)R and NRC(O)NR₂, whereineach R is independently selected from H and (C₁-C₈)alkyl; R³ and R⁴ areeach independently (C₁-C₄)alkyl or are optionally combined with thenitrogen atom to which each is attached to form a ring selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperidine,imidazoline, piperazine and morpholine, each of said rings beingoptionally substituted with from one to three substituents selected fromthe group consisting of (C₁-C₄)alkyl, phenyl, phenyl(C₁-C₄)alkyl,hydroxy, 18 hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl anddi(C₁-C₄)alkylamino(C₁-C₄)alkyl; and the wavy line indicates the pointof attachment to L.
 6. A method in accordance with claim 5, wherein L isselected from the group consisting of —NH—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂—,—OCH₂CH(OH)CH₂— and —NHCH₂CH₂CH₂—; R¹ and R² are each ethyl; thesubscript n is an integer of from 1 to 2; each R⁵ is a substituentindependently selected from the group consisting of halogen, NO₂, CN,CO₂R and C(O)R; wherein each R is independently selected from H and(C₁-C₄)alkyl; and R³ and R⁴ taken together with the nitrogen atom towhich each is attached form a 5- or 6-membered ring selected from thegroup consisting of pyrrolidine, piperidine and morpholine.
 7. A methodin accordance with claim 1, wherein said compound has the formula:

wherein the subscripts m and n are each independently integers from 1 to2; and R³ and R⁴ are each independently selected from the groupconsisting of (C₁-C₄)alkyl, or when taken together with the nitrogenatom to which each is attached, form a ring selected from the groupconsisting of aziridine, azetidine, pyrrolidine and piperidine which isoptionally substituted with one or two (C₁-C₄)alkyl groups.
 8. A methodin accordance with claim 1, wherein said compound inhibits chemokinebinding to US28 on the surface of an infected cell or virion.
 9. Amethod in accordance with claim 8, wherein said chemokine isfractalkine.
 10. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound having formula I:

wherein Ar is a substituted or unsubstituted 5-14 membered heteroarylgroup or a substituted or unsubstituted (C₆-C₁₄)aryl group; L is asubstituted or unsubstituted linkage having from two to fourteencontiguous chain atoms selected from the group consisting of C, N, O, Pand S; and R¹ and R² are each independently selected from the groupconsisting of (C₁-C₄)alkyl; wherein any alkyl portions of L, R¹ and R²are optionally substituted with from one to four substituents selectedfrom halo, OR′, SR′, S(O)pR′, and CO₂R′, in which R′ is H or a(C₁-C₄)alkyl group, and the subscript p is 1 or 2; or R¹ and R² areoptionally combined with the nitrogen atom to which each is attached toform a ring selected from aziridine, azetidine, pyrrolidine, piperidine,imidazoline, piperazine and morpholine, each of the rings beingoptionally substituted with from one to three substituents selected from(C₁-C₄)alkyl, phenyl, phenyl(C₁-C₄)alkyl, hydroxy, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl and di(C₁-C₄)alkylamino(C₁-C₄)alkyl.
 11. Apharmaceutical composition in accordance with claim 10, wherein L isselected from the group consisting of —N═C(CH₃)—, —NH—CH(CH₃)CH₂CH₂CH₂—,—CH₂CH₂—, —OCH₂CH(OH)CH₂— and —NHCH₂CH₂CH₂—; R¹ and R² are each ethyl;and Ar is a substituted phenyl having the formula:

wherein the subscript q is an integer of from 0 to 3; each R⁵ is asubstituent independently selected from the group consisting of halogen,NO₂, CN, R, OR, NR₂, CO₂R, C(O)R, OC(O)R, NRC(O)R and NRC(O)NR₂, whereineach R is independently selected from H and (C₁-C₈)alkyl; R³ and R⁴ areeach independently (C₁-C₄)alkyl or are optionally combined with thenitrogen atom to which each is attached to form a ring selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperidine,imidazoline, piperazine and morpholine, each of said rings beingoptionally substituted with from one to three substituents selected fromthe group consisting of (C₁-C₄)alkyl, phenyl, phenyl(C₁-C₄)alkyl,hydroxy, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl anddi(C₁-C₄)alkylamino(C₁-C₄)alkyl; and the wavy line indicates the pointof attachment to L.
 12. A pharmaceutical composition in accordance withclaim 10, wherein L is selected from the group consisting of—NH—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂—, —OCH₂CH(OH)CH₂— and —NHCH₂CH₂CH₂—; R¹and R² are each ethyl; the subscript n is an integer of from 1 to 2;each R⁵ is a substituent independently selected from the groupconsisting of halogen, NO₂, CN, CO₂R and C(O)R; wherein each R isindependently selected from H and (C₁-C₄)alkyl; and R³ and R⁴ takentogether with the nitrogen atom to which each is attached form a 5- or6-membered ring selected from the group consisting of pyrrolidine,piperidine and morpholine
 13. A pharmaceutical composition in accordancewith claim 10, wherein said compound has the formula:

wherein the subscripts m and n are each independently integers from 1 to2; and R³ and R⁴ are each independently selected from the groupconsisting of (C₁-C₄)alkyl, or when taken together with the nitrogenatom to which each is attached, form a ring selected from the groupconsisting of aziridine, azetidine, pyrrolidine and piperidine which isoptionally substituted with one or two (C₁-C₄)alkyl groups.
 14. Acompound having the formula:

wherein the subscripts m and n are each independently integers from 1 to2; R¹ and R² are each independently selected from the group consistingof (C₁-C₄)alkyl, wherein the alkyl portions are optionally substitutedwith OH or (C₁-C₄)alkoxy groups; or R¹ and R² are optionally combinedwith the nitrogen atom to which each is attached to form a ring selectedfrom the group consisting of aziridine, azetidine, pyrrolidine,piperidine, imidazoline, piperazine and morpholine, each of said ringsbeing optionally substituted with from one to three substituentsselected from the group consisting of (C₁-C₄)alkyl, phenyl,phenyl(C₁-C₄)alkyl, hydroxy, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl and di(C₁-C₄)alkylamino(C₁-C₄)alkyl; and R³and R⁴ are each independently selected from the group consisting of(C₁-C₄)alkyl, or when taken together with the nitrogen atom to whicheach is attached, form a ring selected from the group consisting ofaziridine, azetidine, pyrrolidine and piperidine which is optionallysubstituted with one or two (C₁-C₄)alkyl groups.
 15. A compound of claim14, wherein m and n are each 1; R¹ and R² are each ethyl; R³ and R⁴ arecombined with the nitrogen atom to which each is attached to form apyrrolidine ring; and wherein said compound has the R-stereochemistry atthe carbon bearing the hydroxy group.
 16. A compound of claim 14,wherein m and n are each 1; R¹ and R² are each ethyl; R³ and R⁴ arecombined with the nitrogen atom to which each is attached to form apyrrolidine ring; and wherein said compound has the S-stereochemistry atthe carbon bearing the hydroxy group.